Anticancer carrier-linked prodrugs in clinical trials

Abstract

Coupling of low molecular weight anticancer drugs to antibodies, serum proteins or polymers through a cleavable linker has been an effective method for improving the therapeutic index of cytotoxic established agents. Modern drug-antibody conjugates that have recently entered clinical trials have primarily used highly potent drugs such as calicheamicin or maytansins. Gemtuzumab ozogamicin, a conjugate of calicheamicin and an anti-CD33 humanized antibody, is the first drug-antibody conjugate to receive market approval. Drug conjugates that have undergone clinical assessment include N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates with doxorubicin, camptothecin, paclitaxel and Pt(II) complexes, poly(ethylene glycol) conjugates with camptothecin and paclitaxel, polyglutamate conjugates with paclitaxel and camptothecin, a methotrexate-albumin conjugate and an albumin-binding doxorubicin prodrug. This review summarizes the Phase I-III studies that have been performed with these macromolecular prodrugs.